Hi all,
Chimeric Therapeutics (ASX:CHM) develops CAR T cell therapies, a form of immunotherapy where a patient’s own T cells are genetically engineered to better recognize and destroy cancer cells.
How CAR T Therapy Works
Blood is drawn from the patient and T cells are isolated (leukapheresis).
These T cells are genetically modified in the lab to express a chimeric antigen receptor (CAR) that targets a specific cancer antigen.
The engineered CAR T cells are expanded (multiplied) in th laboratory.
CARs combine an antigen recognition domain (often from antibodies or peptides like chlorotoxin) with intracellular signaling domains that activate T cells upon antigen binding, prompting them to kill the cancer cell.
Targeting CDH17 (e.g., with RNA interference or CAR-based therapies) can inhibit tumor growth, reduce metastasis, and induce cancer cell apoptosis in preclinical models.
CDH17 is considered an attractive biomarker and therapeutic target for aggressive gastrointestinal malignancies.
Ok so how does the proprietary drugs work.
https://www.cancer.org/cancer/managing-cancer/treatment-types/immunotherapy/car-t-cell1.html
In part 1/2/3 of Generation 2 Car T therapy we have alluded that an infusion of T cells kill cancer cells. Is there any untoward targets with Cdh17?
There is no clinical evidence to date that CDH17 CAR T therapy causes widespread B cell depletion or immunodeficiency, unlike therapies targeting CD19 (which is present on all B cells)
Today we explore generation 3 and touch on a few interesting subjects.
Phase 1/2 trial (NCT06055439):
Lymphodepletion (3-day chemotherapy) precedes CAR-T infusion to enhance efficacy to all our patients .
Lymphodepletion therapy means giving a short course of chemotherapy before CAR T-cell treatment to lower the number of certain immune cells (like T cells) in your body. This “clears space” so the new CAR T cells can grow and work better when they’re put in, making the treatment more effective. In simple terms: it’s like weeding a garden before planting new seeds, so the new plants (CAR T cells) have room and nutrients to thrive. Drugs used are fludarabine and cyclophosphamide.
Dose escalation of Cdh17 starts at 50 million CAR-T cells, with early safety data expected within 28 days post-infusion. So far so good
The potential for CDH17-targeted CAR-T therapy (e.g., CHM CDH17) to achieve tumor obliteration in early-stage, small neuroendocrine tumors (NETs) within 90 days remains speculative but theoretically plausible under optimal conditions, based on preclinical and early clinical insights.
Complete eradication of established tumors was demonstrated in seven cancer models, including NETs, with no toxicity to healthy tissues.
These experiments used CAR-T cells targeting CDH17, showing rapid tumor regression in mice, though exact timelines were not specified in the research.
Objective response rate (primary endpoint) will assess tumor shrinkage, but no interim results are yet reported.
Time to response in solid tumors (e.g., colorectal) historically ranges from weeks to months for partial responses.
When a tumor has more even (homogeneous) CDH17 expression and better blood supply (vascularization), CAR-T cells can get into the tumor more easily and quickly. This is because:
The CAR-T cells have an easier time finding and attacking cancer cells when those cells all show the same marker (CDH17).
Good blood flow helps CAR-T cells travel into the tumor.
In contrast, large, bulky tumors often have uneven marker expression and poor blood supply, making it harder for CAR-T cells to get in and work effectively.
Realistic Expectations for 90-Day Outcomes
Partial response: A 30–50% reduction in tumor size within 90 days is achievable if the therapy replicates preclinical efficacy.
Complete response:
Possible for sub centimetre tumors (e.g., <1 cm) with high CDH17 expression, based on preclinical eradication of similarly sized models.
Less likely for 1–2 cm tumors without adjunctive therapies (e.g., checkpoint inhibitors to sustain CAR-T activity)
Pseudoprogression (initial tumor swelling due to immune infiltration) may complicate early imaging assessment, thus a time delay on diagnosis.
Limitations and Unknowns
No human data: The ongoing trial has not yet reported efficacy results for NETs.
Durability: Preclinical models show sustained remission, but human immune persistence may require booster infusions.
Toxicity: While preclinical studies show no on-target/off-tumor effects, human trials must confirm this safety profile. Seems like none at present which is rare for novel Car T therapy. This is a very good " thing".
So being speculative . Obliteration of very small, early-stage NETs within 90 days is biologically plausible but remains unproven. Definitive answers will emerge from the ongoing CHM CDH17 trial, with early efficacy data expected soon.
Key Evaluation " possible " Timepoints
Primary Efficacy Assessment (Phase 2):
Objective response rate (ORR) using RECIST 1.1 criteria (e.g., ≥30% reduction in tumor diameter) at a predefined timepoint (likely 12–16 weeks post-infusion based on solid tumor CAR-T benchmarks).
Failure threshold: If the ORR in the NET cohort falls below the Simon 2-Stage minimum (e.g., <20% response required to proceed to Stage 2), the cohort would be deemed unsuccessful.
Early Failure Indicators:
28-day safety window (Phase 1): Dose-limiting toxicities (DLTs) supersede efficacy evaluation here. Persistent grade ≥3 cytokine release syndrome (CRS) or neurotoxicity could halt the trial. ( That won't happen in my research, so negate that).
Day 90 CT/MRI: No measurable shrinkage (e.g., <10% reduction) or progression in ≥50% of patients would signal inadequate biological activity.
Tumor Size Reduction vs. Drug Persistence
CAR-T expansion/duration:
Peak activity: CAR-T cells typically proliferate maximally within 7–14 days post-infusion, with functional persistence for weeks to months.
Therapeutic window: Tumor shrinkage should initiate within 4–8 weeks if CAR-Ts are effective. Lack of response by 8–12 weeks suggests failure ( speculation but could be true)
Residual disease:
Stable disease (SD) at 12–16 weeks might not constitute failure if accompanied by biomarker improvements (e.g., declining CDH17 expression).
Progressive disease (PD) at any point post-infusion would count as treatment failure.
Trial-Specific Failure Criteria
Phase 1:
Primary failure: Inability to establish a recommended Phase 2 dose or manufacturing failures
When a tumor has more even (homogeneous) CDH17 expression and better blood supply (vascularization), CAR-T cells can get into the tumor more easily and quickly. This is because:
The CAR-T cells have an easier time finding and attacking cancer cells when those cells all show the same marker (CDH17).
Good blood flow helps CAR-T cells travel into the tumor.
In contrast, large, bulky tumors often have uneven marker expression and poor blood supply, making it harder for CAR-T cells to get in and work effectively6710
So the reason I bought into CHM was how many ASX companies or Worldwide companies who specialise in oncology have successful phase 1 top line results that are valued below 100 million AUD ?. Answer is none. CHM MC $9 million approximately. You get the picture. I then started to look at futuristic results combined with objective science and realised that CHM is close to achieving top line results. The mathematics of the multiplication of the T cells once infused piqued my research and therefore I deemed it a valid investment proposition. More on that soon.
Back to the future Part 3.
Stage 1 failure (NET cohort): If ≤2/6–10 patients achieve partial response (PR) by 12–16 weeks, the cohort may close.
Combination potential: Trial protocols may allow salvage therapies (e.g., checkpoint inhibitors) after confirmed progression, complicating failure attribution.
So in summary, definitive failure would be declared if the trial fails to meet its primary ORR endpoint at the protocol-specified assessment time (likely 3–4 months post-treatment), though early progression or toxicity could halt specific cohorts sooner. Interim analyses (e.g., at Day 90) would inform futility decisions.
After establishing a recommended Phase 2 dose, three indication-specific Simon 2-Stage cohorts will be initiated in (1) Gastric cancer (2) Colorectal cancers and (3) NETs of the midgut or hindgut to further characterize the safety and assess the efficacy of CHM CDH17 CAR T-cells. This is an ongoing first-in-human multi-center clinical trial of CHM CDH17, a CDH17 directed autologous CAR T-cell product candidate, enrolling subjects with advanced GI cancers that express CDH17.
Clinical trial information: NCT06055439.
Phase 2 cohorts: The Simon 2-Stage design for NETs may indirectly exclude bulky tumors if early responders are primarily smaller masses, but this is speculative
The Simon two-stage design itself does not inherently exclude bulky tumors, but its structure creates indirect selection pressures that could favor smaller masses in practice. Whether this strategy improves FDA approval prospects depends on trial execution and endpoint alignment:
Key Considerations
Simon Design Mechanics:
Stage 1: Enrolls a small cohort (e.g., 10–15 patients) to assess early efficacy signals (e.g., ≥2 responses in 10 patients to proceed to Stage 2).
Stage 2: Expands enrollment if Stage 1 meets predefined response thresholds.
Implicit bias: Smaller tumors (e.g., <5 cm) with higher CDH17 homogeneity and better vascularization may show stronger early responses, indirectly skewing enrollment toward these cases in Stage 2.
FDA Approval Strategy: Pros
Early futility stopping reduces patient exposure to ineffective therapies, aligning with FDA’s risk-benefit priorities. ( Appreciate its more of a con, but early failure is better for our patient cohort if it needs to be, I look at all the possibilities)
Efficiency: Smaller sample sizes (e.g., 20–40 total patients) expedite Phase 2 completion, accelerating regulatory submissions.
Cons:
Heterogeneous tumors: Excluding bulky masses (even unintentionally) may limit generalizability, raising FDA concerns about real-world applicability.
Endpoint selection: ORR (objective response rate) in small tumors may not predict survival benefits required for full approval.
Mitigation Strategies:
Stratification: Pre define subgroups by tumor size (e.g., <5 cm vs. ≥5 cm) to ensure proportional enrollment.
Adaptive modifications: Use Bayesian mathematical designs to dynamically adjust enrollment criteria based on emerging size-response correlations.
Combination endpoints: Pair ORR with duration of response or PFS (progression-free survival) to demonstrate clinical meaningfulness.
Recommendations
Design transparency: Justify historical control rates (e.g., ORR benchmarks for NETs) and predefine subgroup analyses in the protocol.
Real-world relevance: Ensure Stage 2 includes proportionate representation of bulky tumors if biologically plausible (e.g., CDH17-positive large masses.
Regulatory alignment: Engage FDA early via pre-IND meetings.
Conclusion
A well-executed Simon design with intentional safeguards against size bias could support accelerated approval if early ORR signals are robust. However, FDA approval ultimately requires clinically meaningful outcomes (e.g., survival, quality of life) and representative patient populations, not just statistical efficiency. Combining Simon’s design with adaptive elements and rigorous subgroup analyses would strengthen the application.
Ok we have looked at most clinical juicy bits, the best is to come.
How many T cells to kill a cancer cell ?
Minimum: 1–3 T cells per cancer cell (if fully functional, antigen-specific, and unopposed by immunosuppression).
Realistic: 10–50 T cells per cancer cell (accounting for exhaustion, poor infiltration, and Treg activity. ( Think of tregs as T cells psychologists, they calm the immune response)
These estimates assume idealized conditions rarely met in vivo, emphasizing why immunotherapies often require combinatorial strategies to enhance T cell efficacy.
Speculative calculation for a 10 cm neuroendocrine tumor (NET):
Assuming a simplified model) and typical cell parameters:
Cell density:
Tumors generally contain 10⁸–10⁹ cells/cm³NETs often show compact architecture due to desmoplastic reactions, suggesting higher packing density.
Assumed density: ~5 × 10⁸ cells/cm³ (mid-range estimate).
Heterogeneity: NETs often contain stroma, immune cells, and vascular components, reducing functional cancer cell density.
Growth patterns: Many NETs are slow-growing (Ki-67 index ≤20% in well-differentiated cases), implying lower mitotic activity than aggressive carcinomas.
Clinical relevance: A 10 cm NET is exceptionally large (most are <3 cm at diagnosis, likely representing long-standing disease with complex microenvironmental interactions.
This estimate focuses on total cellularity, not functional tumor burden, as NETs often include dormant or non-proliferating cells.
Now onto the crux of the mechanics.
The human body contains approximately 5 × 10¹¹ T cells (500 billion) at any given time, based on recent comprehensive analyses of immune cell populations. This estimate includes all T cell subtypes (helper, cytotoxic, regulatory, etc.) distributed across lymphoid tissues, blood, and peripherals.
Key reasons why CDH17-targeted cell therapies (e.g., 50 million infused cells) can impact billions of cancer cells:
Take note :
CAR-NK/CAR-T cells expand in the body after infusion, often reaching 10- to 100-fold increases in number.
Serial killing: Each engineered immune cell can eliminate multiple cancer cells through target engagement.
CDH17 blockade directly disrupts cancer cell survival pathways (e.g., Wnt/β-catenin)reducing tumor growth independently of immune cells.
CD47 co-blockade prevents "don't eat me" signals, enhancing phagocytosis of cancer cells by macrophages and NK cells.
Bystander effects:
Cytokine release from activated immune cells recruits endogenous T cells and NK cells to the tumor.
Antigen spread: Dying cancer cells release new antigens, broadening immune responses beyond CDH17.
Tumor microenvironment modulation:
CDH17 inhibition weakens cell-cell adhesion , increasing susceptibility to immune attack
Wnt pathway suppression (via CDH17 targeting) reduces stemness and metastatic potential. So we are using the GPS signal to change cancer cells structure.
Example calculation:
If 50 million CDH17-CAR-NK cells expand to 5 billion in vivo and each kills 10–100 cancer cells, they could eliminate 50–500 billion cancer cells—consistent with tumor sizes discussed earlier. However, combinatorial effects (above) amplify this impact beyond simple arithmetic.
Critical factors:
Tumor accessibility: Solid tumors often limit immune cell infiltration, necessitating strategies to overcome physical barriers.
Antigen density: High CDH17 expression in gastrointestinal cancers ensures target availability.
Dose timing: Multiple infusions or continuous therapies compensate for immune cell exhaustion.
This explains why quality (cell engineering, target selection) often outweighs quantity (raw cell numbers) in immunotherapy efficacy.
Potential effects of 450 million CDH17-targeted cell infusion on moderate neuroendocrine tumor (NET) burden, based on current preclinical and clinical insights ( CHM plan)
Mechanistic advantages
Enhanced tumor penetration:
CDH17 specificity allows CAR-T/NK cells to selectively bind NET cells while avoiding healthy tissues (due to antigen "masking" in normal epithelial tight junctions).
Third-generation CAR design (with optimized costimulatory domains like 4-1BB/CD28) improves persistence and cytotoxicity. Remember this is our novel patent. No one Company is at this level for NETs in my research.
Third-generation CAR T cells are specially engineered immune cells designed to fight cancer more effectively. They combine two "costimulatory domains"-CD28 and 4-1BB-which act like extra "on switches" to help the T cells:
CD28 helps the CAR T cells activate quickly and multiply fast.
4-1BB helps the CAR T cells survive longer and stay active in the body.
Proliferative scaling:
In the body expansion: CAR-T cells typically multiply 10–100× post-infusion in responders. A 450 million dose ( CHM planned forward dose) could theoretically expand to 4.5–45 billion effector cells, enabling coverage for ~10⁹–10¹⁰ cancer cells (assuming 10–100 kills per CAR-T cell). We mentioned tumour size a few paragraphs back .
Synergy with tumor size: For a "moderate" NET burden (e.g., ~10⁹–10¹⁰ cells, roughly 2–20 cm³ volume), this scaled activity aligns with preclinical models showing complete eradication of similarly sized CDH17+ tumors.
Durability:
Memory T cell formation may sustain anti-tumor activity beyond the initial infusion.
Tumor microenvironment modulation (e.g., reduced immunosuppressive signals post-CD47 blockade combo) could prolong efficacy.
Limitations and risks
Heterogeneity: NETs with low CDH17 expression may evade therapy.
Physical barriers: Stromal density in NETs might limit CAR-T infiltration, necessitating adjunct therapies (e.g., collagenase pretreatment).
Dose-response variability: While higher doses (450M vs. 50M) improve tumor control in principle, saturation effects and immune exhaustion risks require careful clinical monitoring.
Projected outcomes
Best-case: Significant tumor regression (≥50% volume reduction) or complete remission in CDH17-high NETs, as seen in preclinical xenografts.
Realistic: Stable disease or partial response in most patients, with potential for progression-free survival extension.
Failure modes: Antigen escape (CDH17 loss) or T cell exhaustion could lead to relapse.
Conclusion: A 450M CDH17-CAR-T infusion has strong biological rationale for moderate NETs, but clinical results will depend on CDH17 expression levels, tumor accessibility, and combinatorial strategies. Early-phase trial data will be critical for validation.
Potential effects of 450 million CDH17-targeted cell infusion on moderate neuroendocrine tumor (NET) burden, based on current preclinical and clinical insights:
Mechanistic advantages
Enhanced tumor penetration:
Limitations and risks
Heterogeneity: NETs with low CDH17 expression may evade therapy. We are only targeting high cancer Cdh17 expression.
Analysis of CHM's 450 million CD
CH17 CAR-T dose for 10 cm NETs
Current clinical context
The ongoing Phase 1/2 trial (NCT06055439) starts at 50 million CAR-T cells to establish safety. Preclinical data show CDH17-targeted CAR-T/NK cells achieve complete regression in multiple solid tumor models at doses scalable to human equivalents, supporting higher-dose exploration.
Rationale for 450 million cells
Dose-response relationship:
Preclinical scaling: Effective doses in mice (~10⁷ cells) translate to ~10⁸–10⁹ cells in humans (accounting for body mass and tumor size).
Tumor burden: A 10 cm NET (~2.6 × 10¹¹ cells) demands high effector T cell numbers to achieve meaningful cancer cell engagement. Remember this seems to be our maximum tumour target. Smaller tumours have far less cancer cells.
Manufacturing feasibility: Producing 450 million autologous CAR-T cells is technically achievable with current platforms.
Safety buffer: Preclinical studies report no toxicity at doses suppressing large tumors, de-risking escalation to 450 million.
Antigen heterogeneity: CDH17 expression in NETs is variable, patient selection via biomarker screening will be critical.
Exhaustion risks: High CAR-T doses could accelerate dysfunction without proper costimulatory domains (4-1BB/CD28 . I believe we have that covered)
Conclusion
The 450 million dose is biologically plausible for 10 cm NETs based on preclinical scaling and CAR-T expansion dynamics. However, clinical validation is essential—Phase 1 data will determine whether this dose achieves sufficient tumor penetration and persistence without excessive toxicity. The CEO’s strategy aligns with emerging CAR-T paradigms for solid tumors but remains hypothesis-driven until trial results mature.
Recommendation: Proceed with 450 million in Phase 2 if Phase 1 shows acceptable safety at lower doses.
I do hope I have explained this to within general reason. It's not an easy topic with trial design overlays and everything else .
Part 5 next week, a quick look at checkpoint inhibitors, CHM
manufacturing and lack of Company competition. That will be a breeze.
Part 6 what's our Company valuation . Has CHM been through that rigour yet?
Much more to come.
Thanks
Kpax
Q
